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ATM-mediated phosphorylation activates the tumor-suppressive function of B56γ-PP2A

G P Shouse1, Y Nobumori, M J Panowicz

  • 1Department of Biochemistry, University of California, Riverside, USA.

Oncogene
|April 5, 2011
PubMed

Insights

DNA damage activates tumor suppressor functions of B56-PP2A phosphatases. ATM kinase phosphorylates B56 subunits, enhancing PP2A activity toward p53 and inhibiting cell proliferation.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • Protein phosphatase 2A (PP2A) is crucial for diverse cellular functions.
  • Specific PP2A holoenzymes containing B56 subunits act as tumor suppressors.
  • Regulatory mechanisms for B56-PP2A tumor suppressor activity remain unclear.

Purpose of the Study:

  • To elucidate the regulatory mechanisms governing B56-PP2A tumor-suppressive function.
  • To investigate the role of ATM in regulating B56-PP2A activity after DNA damage.
  • To identify specific B56 subunits and phosphorylation sites involved in this process.

Main Methods:

  • Investigated ATM-mediated phosphorylation of B56 subunits (B56γ3, B56γ2, B56δ) post-DNA damage.
  • Assessed the impact of B56γ3 phosphorylation at Ser510 on PP2A complex formation and p53 substrate targeting.
  • Examined the interplay between ATM, MDM2, and B56γ3 ubiquitination and stability.
  • Evaluated the effect of Ser510 phosphorylation on B56γ3's ability to inhibit cell proliferation and anchorage-independent growth.

Main Results:

  • ATM directly phosphorylates B56γ3, B56γ2, and B56δ following DNA damage.
  • Phosphorylation of B56γ3 at Ser510 increases B56γ3-PP2A complexes, directing activity towards p53 and activating its tumor-suppressive functions.
  • ATM-mediated phosphorylation of B56γ3 blocks MDM2-dependent ubiquitination, leading to B56γ3 upregulation.
  • Ser510 phosphorylation significantly enhances B56γ3's inhibition of cell proliferation and anchorage-independent growth.

Conclusions:

  • ATM-dependent phosphorylation is a key regulator of B56-PP2A tumor-suppressive function.
  • This pathway provides mechanistic insight into how DNA damage activates PP2A's role in tumor suppression.
  • A model for parallel regulation of p53 and B56γ3 is proposed, highlighting their coordinated role in tumor suppression.

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